WO2014170915A1

WO2014170915A1 - Insect repellents

Info

Publication number: WO2014170915A1
Application number: PCT/IN2014/000244
Authority: WO
Inventors: Dumbala Srinivasa REDDY; Kishor Laxman HANDORE; Seetharam Singh BALAMKUNDU; Avalokiteswar Sen; Pushpa Vijay Pawar; Mary Joseph
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2013-04-17
Filing date: 2014-04-17
Publication date: 2014-10-23
Anticipated expiration: 2015-10-17

Abstract

Disclosed herein are the novel insect repellents of formula (I) to control the spread of various tropical diseases and to the process of preparation thereof wherein R, Rl, R3, R4 represents hydrogen or alkyl; R2 is selected from hydrogen, alkyl, C02R, C02H; 'n' is 1, 2, or 3; wherein any two of Rl, R2, R3 or R4 may form a 3-8 membered carbocyclic ring which may optionally be substituted or may contain a heteroatom; X is selected from O, S or CH2; ' ' represents a single or double bond; wherein, either of the ring in formula (I) may additionally contain at least one carbonyl group.

Description

INSECT REPELLENTS

FIELD OF THE INVENTION

The present invention relates to insect repellent compound of general formula I to control the spread of various tro ical diseases.

General Formula I

Particularly, present invention relates to process for the preparation of insect repellent compound of general formula I. ·

BACKGROUND AND PRIOR ART OF THE INVENTION Nootkatone is obtained from essential oils of plants such as grapefruit, vetiver grass, and Alaskan yellow cedar, as well as by chemical synthesis methods, and is commonly used in foods, cosmetics, and pharmaceuticals. But nootkatone's potential to kill ants, termites, mosquitoes, cockroaches, and ticks, including Ixodesscapularis (blacklegged tick), whose bite can transmit bacteria that cause Lyme disease in humans and other animals has also been demonstrated by various research groups.

In the past 5 years, an average of 20,000 Lyme disease cases have been reported annually, whereas the number of reported Lyme disease cases reached an all-time high of35,000 in 2008 (CDC 2010).

An article titled, "Potential target site activity of nootkatone and tetrahydronootkatone on Formosan Subterranean Termite (Isoptera: Rhinotermitidae)" by Sanaa Ibrahim et al. in African Crop Science Conference Proceedings, 2007, Vol. 8, pp. 1 125- 1 131 reports the higher toxicity with tetrahydronootkatone in the biological assays and higher AChE- activity in the biochemical assays were achieved compared to nootkatone. In topical application assays, tetrahydronootkatone was observed 1.7- 2.6 fold more toxic to workers than nootkatone. It also supports the hypothesis that AChE stimulation is a possible target site for nootkatone and tetrahydronootkatone.

In an article titled, "Structural requirements for repellency: norsesquiterpenes and sesquiterpenoid derivatives of nootkatone against the Formosan subterranean termite (Isoptera: Rhinotermitidae)" by Betty CR Zhu, Gregg Henderson, AnneMSauer, William Crowec and Roger A Laine in Pest Manag Sci, 2010, 66, 875-878 reports four derivatives of nootkatone having very high \repellency and toxicity to C. formosanus, 9 times the potency of the primary compound nootkatone. Four other compounds have between 2 and 3 times the repellency of nootkatones, and three compounds are equal in their repellency to nootkatone. The results of this article indicate that minor structural variations in nootkatone derivatives show significant differences in their repellency to Coptotermesformosanus, indicating the presence of a specific binding site.

In an another article titled, " Lignin + Nootkatone = Dead Ticks" by Jan Suszkiw in Agricultural Research, Jan, 201 1 , pp 10- 1 1 reports the toxicity of nootkatone to four target species of tick. This article clearly reports the importance of nootkatone that if the costs of obtaining nootkatone can be reduced, the essential oil could be especially attractiveto a burgeoning organic lawn care movement in the Northeast. Rather than a stand-alone defense, however, nootkatone would be integrated with other measures as part of a "biorational" approach to insect control.

Recently, an article titled, "Efficacy of Plant-Derived and Synthetic Compounds on Clothing as Repellents againstlxodesscapularis and Amblyommaamericanum (Acari: Ixodidae)" by Robert A. Jordan, Terry L. Schulzeand Marc C. Dolan in J. Med. Entomol. 49(1), 101 - 106, (2012) reported the comparison of the relative repellent activity of two natural product compounds (nootkatone and carvacrol) with commercially available plant- derived (EcoSMART organic insect repellent) and permethrin-based (Repel Permanone) repellents against adult Ixodesscapularis Say and Amblyommaamericanum (L.) (Acari: Ixodidae ) by using treated cover alls. The results showed that nootkatone was the most effective against both species followed in order of activity by Permanone, EcoSMART, and carvacrol. EP1355895B1 discloses pesticidal composition for controlling arthropod pests selected from valencene, nootkatone, nootkatol, epinootkatol, nootkatene, 13-hydroxy-valencene, valencene- 1 1 , 12-epoxide, valencene- 13-aldehyde, or nootkatone- 1 , 10- 1 1 , 12-diepoxide.

Furthermore, the chemical processes in the art for synthesis of nootkatone and the analogues are lengthy, cumbersome and not industrially feasible.

In view of the above, there still remains a need in the art for effective insect repellents capable of controlling a variety of pests that is relatively safe for humans, animals, plants, and the environment. Also, the present invention envisages to provide a process for synthesis of nootkatone and its novel analogues of formula (I) that ameliorates the drawbacks of the known processes and provides a simple, short, economical process in high yield and purity.

OBJECT OF THE INVENTION

The main objective of the present invention is to provide insect repellent compound of general formula I belonging to Nootkatone.

Another object of the current invention is to provide the process for the preparation of Nootkatone, Noreremophilane and its analogues of general formula I having insect repellent activity. BRIEF DESCRIPTION OF THE FIGURES

Scheme 1 represents the process steps for preparation of compounds of general formula I. SUMMARY OF THE INVENTION

Accordingly, present invention provides a compound of general formula (I)

wherein R, Rl , R3, R4 represents hydrogen or alkyl (C 1-C4);

R2 is selected from hydrogen, alkyl (C 1 -C4), COOR, COOH;

'n' is 1 , 2, or 3;

wherein any two of Rl , R2, R3 or R4 may form a 3-8 membered carbocyclic ring which may optionally be substituted or may contain a heteroatom selected from O or N;

X is selected from O, S or CH₂;

' ' represents a single or double bond;

wherein, either of the ring in formula (I) may additionally contain atleast one carbonyl group.

In an embodiment of the present invention, representative compounds comprising: l-((4aR,8R,8aS)-8,8a-dimethyl-3,4,4a,7,8,8a-hexahydronaphthalen-2- yl)ethanone (la);

l-((3aS,4R,7aR)-4-methyl-3a,4,5,7a-tetrahydro- l H-inden-2-yl)ethanone (Ic); aR)-4-ethyl-3a,4,5,7a-tetrahydro- l H-inden-2-yl)ethanone

7-Acetyl- l ,8a-dimethyl-4a,5, 6,7,8, 8a-hexahydronaphthalen-2(l H)-one

(ie);

(4R,4aR)-6-acetyl-4,4a-dimethyl-4,4a,7,8-tetrahydronaphthalen-2(3H)- one (If);

(3aS,4R,7aR)-ethyl-2-acetyl-3a,4,5,7a-tetrahydro- l H-indene-4- carboxylate (Ig); 4,5,7a-tetrahydro- 1 H-ihden-2-yl)ethan- 1 -one (Ih) ;

,4a,7,8,8a-hexahydronaphthalen-2-yl)ethan- l -one (Ii);

l-(8-Methyl-3,4,4a,7,8,8a-hexahydronaphthalen-2-yl)ethan- l -one (Ij);

H

a,7,8,8a-hexahydronaphthalen-2-yl)ethan- l-one (Ik);

rahydro- lH-inden-2-yl)ethan- l-one (II);

-Hexahydronaphthalen-2-yl)ethan- l-one (Im);

1 -(4-Ethyl-3a-methyl-3a,4,5,7a-tetrahydro- 1 H-inden-2-yl)ethan- 1 -one

l-(8-Ethyl-8a-methyl-3,4,4a,7,8,8a-hexahydronaphthalen-2-yl)ethan- l - one (Io);

-Ethyl-4-propyl-3a,4,5,7a-tetra ydro- l H-inden-2-yl)ethan- l -one

1 -(8a-Ethyl-8-propyl-3,4,4a,7,8,8a-hexahydronaphthalen-2-yl)ethan- 1 - one (Iq);

1 -(8,8a-Dimethyl- 1 , 2,3,4, 4a,7, 8,8a-octahydronaphthalen-2-yl)ethan- 1- one (Ir);

thyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (Is).

In another embodiment of the present invention, said compound exhibit insect repellent activity to control the spread of various tropical diseases.

In yet another embodiment of the present invention, said compound exhibit protection period at 0.25 mg/cm² dose is in the range of 2 to 4.2hr.

In yet another embodiment of the present invention, said compound exhibit protection period at 0.5 mg/cm² dose is in the range of 2 to 6.2 hr. In yet another embodiment, present invention provides a simple, short, economical process for synthesis of compounds of the general formula I comprising the steps of: subjecting a mixture of diene (N) and an aldehyde (M) in dry organic solvent to Diels Alder reaction in presence of BF₃.0Et2 at - 78°C, raising the temperature to room temperature in the range of 23 to 2 °C to obtain an intermediate (P);

wherein R l , R3 represents hydrogen or alkyl (C 1 -C3) ; R2 is selected from hydrogen, alkyl (C 1 -C3), COOR where R is selected from hydrogen, alkyl (C 1 -C3) , COOH .

'n' is 1 , 2, or 3; b. dissolving the intermediate (P) of step (a) in methanol at 0°C followed by treating with 15% KOH to obtain compounds la-Id, Ig- Iq re resented by general formula (Q);

os-Hyd lindanes {n - 1 )

cis-DecaHns (n - 2)

Q

wherein R2 is selected from hydrogen, alkyl (C 1 -C4) , COOR or COOH and R, R l , R3 represents hydrogen or alkyl(C l -C4); subjecting (la) to allylic oxidation using PDC (Pyridinium dichromate) and 'BuOOH in benzene to afford compounds (If) and ketone (S), treating (la) with Na in liq.NH3 followed by reacting with K2CO₃ and MeOH to obtain (Ir);

e. subjecting (Ir) to allylic oxidation using PDC and 'BuOOH yielded (Is) and (Ie) in the ratio 9: 1 followed by separation; f. adding potassium tert-butoxide to a suspension of methyltriphenylphoshonium bromide in dry THF to obtain a canary yellow color solution followed by addition of (Is) in THF at 0°C to yield (±) nootkatone (7);

g. hydrogenating compound (lb) with Wilkinson's catalyst to afford

(±) noreremophilane.

In yet another embodiment, present invention provides a pharmaceutical composition for repelling or killing insects comprising compounds of general formula (I), together with carrier and other excipients.

In yet another embodiment, present invention provides use of compounds of general formula (I) for repelling or killing insects. DETAILED DESCRIPTION OF THE INVENTION

The present invention provide insect repellent compound of general formula I belonging to Nootkatone.

General formula I

wherein

R, Rl , R3, R4 represents hydrogen or alkyl (C1-C4);

R2 is selected from hydrogen, alkyl (C 1-C4), COOR, COOH;

'n'is 1 , 2, or 3;

X is selected from O, S or CH2;

' ' represents a single or double bond;

wherein, either of the ring in formula (I) may additionally contain atleast one carbonyl group. Natural products based on cis- hydrindane/ ds-decalin possess chemically differentiated double bonds due to which the compounds exhibit various functionalities and stereochemical patterns. Introducing vicinal groups and stereochemistry is key to the synthesis of compounds having ci^'s-hydrindane/ cz^'s-decalin core ring structure. The present invention provides a protecting group-free total synthesis of nootkatone and its analogues using a sequential Diels- Alder /aldol approach in a highly diastereoselective manner.

Present invention discloses a simple, economical and short process for the preparation of a class of compounds, belonging to Nootkatone, of general formula I exhibiting insect repellent property, in good yield and purity comprising the steps of: a. subjecting a mixture of diene (N) and an aldehyde (M) in dry organic solvent (dichloromethane, DCM) to Diels Alder reaction in presence of BF₃,OEt2 at -78°C, raising the temperature to room temperature 23 to 28°C to obtain an intermediate (P); b. dissolving the intermediate of step (a) in methanol at 0°C followed by treating with 15% KOH to obtain compounds la-Id and l g- l q represented by general formula (Q); c. subjecting (la) to allylic oxidation using PDC and 'BuOOH in benzene to afford compounds (If) and ketone (S); d. treating (la) with Na in liq.NH followed by reacting with K2CO3 and MeOH to obtain (Ir); e. subjecting (Ir) to allylic oxidation using PDC and ^tBuOOH yielded (Is) and (Ie) in the ratio 9: 1 followed by separation; f. adding potassium tert-butoxide to a suspension of methyltriphenylphoshonium bromide in dry THF to obtain a canary yellow color solution followed by addition of (Is) in THF at 0°C to yield (±) nootkatone (7); hydrogenating compound (lb) with Wilkinson's catalyst to afford noreremophilane (8). The present invention provides the composition with a carrier containing compounds of general formula (I) for killing or repelling pests. The carrier can be a solid, liquid or a gas carrier, such as a propellant. The carrier is selected from among, but not limited to, water, an alcohol, an aldehyde, an alkane, an alkene, an amide, an amine, a diglyceride, an ester, an ether, a glycol ether, a fat, a fatty acid, a glycol ester, a ketone, lanolin, mineral oil, a monoglyceride, paraffin oil, a polyethylene glycol, petrolatum, a propylene carbonate, silicone, tall oils, a terpene hydrocarbon, a terpene alcohol, a triglyceride, finely divided organic solid material, finely divided inorganic solid materials and mixtures thereof.

The composition may further contain gelling agent, preservatives, colorants and other excipients known in the art for formulation. The compositions for killing or repelling pests can be provided in a form selected from among an aerosol, a bar, a cream, a gel, a liquid, a lotion, a paste, a powder, a roll-on, a sheet, a spray, a stick and a tablet form.

The insecticide or pesticide compositions containing nootkatone and/or an analog of nootkatone of general formula (I) that include a carrier can be present in an amount of at or about 0.1% to at or about 10%, or greater than 10%, or greater than 15%, or greater than 20% or greater than 25% by weight.

The present invention further provides a method for repelling an insect or pest from a location, the composition contains a carrier and from at or about 0.1% to at or about 10% nootkatone or analog of nootkatone of general formula (I), or at least 10%, or at least 15%, or at least 20%, or at least 25% nootkatone and/or analog of nootkatone of formula (I). The composition is formulated for delivery of nootkatone or analog of nootkatone of formula (I) effective for at least 8 hours.

EXAMPLES

Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

EXAMPLE 1 Preparation of l-((4a.R,8R,8aS)-8,8a-dimethyl-3,4,4a,7,8,8a-hexahydron aphthalen-2-yl)ethanone (la)

To a solution of diene 2 (2.7 g, 9.50 mmol) and (£)-2-methylbut- 2-enal 1( 4.1 g, 48.9 mmol) in dry CH₂C1₂ (60 mL) was added BF₃OEt₂ (5.5 g 0.04 mmol) dropwise at -78 °C. The mixture was allowed to warm to room temperature (25°C) and was stirred for 18 h at room temperature (25°C). The CH₂C1₂ layer was washed with 10% aqueous NaHC0₃ (3 * 30 mL) followed by H₂0 (25 mL) and brine (20 mL), dried over Na₂S0₄, concentrated in vacuo. Crude material 3 (intermediate) obtained after the removal of solvent was dissolved in methanol (30 mL), cooled to 0 °C, and treated with 15% KOH (20 mL). After stirring for 2 h at room temperature (25°C) reaction mass was diluted with petroleum ether (100 mL), washed with water (30 mL), I N HC1 (20 mL) and brine (20 mL) dried over Na₂SC>4, concentrated in vacuo. Purification by flash chromatography over silica gel (1 :9; EtOAc-hexanes) afforded dienone la)( 1.6 g, 42%) as light yellow oil.

3

Compound No. lb, lc, Id, lg, lh, li, lj, lk, 11, lm, In, lo, lp, lq are prepared by the process as given in example 1. Starting material, yield and characterization are given in table 1. Table 1

No. Starting Starting Yield (%) Characterization

materials materials

1 2

la 46 IRu_max(film): 1669, 1637, 1452,

1237, 1003 cm-i; *HNMR (500 MHz, CDC1₃) δ 6.64 (s, 1 H), 5.60-5.56

CHO (m, 1 H), 5.53-5.48 (m, l H), 2.28 (s,

3 H), 2.12-2.00 (m, 2 H), 1.93-1.88 (m, 2 H), 1.90-1.63 (m, 3 H), 1.43 (ddd, J = 5.49 Hz, 9.15 Hz, 18.9 Hz ), 1.00 (s, 3 H), 0.96 (d, 3 H, J = 6.4 Hz, 3 H); ^lac MR (125 MHz, CDC1₃) δ 198.0, 149.3, 137.8, 130.1, 125.5, 40.4, 37.3, 34.2, 31.6, 25.6, 25.5, 22.6, 21.1 , 15.1 ; GCMS: 204. lb 48 IR w(nlm): 2962, 1710,

1667, 1461 , 1373, 1019 cm-'; iHNMR (200 MHz, CDCI₃) δ 6.69 (s,

O CHO 1 H), 5.68-5.67 (m, 2 H), 2.85-2.75

(m, 2 H), 2.30 (s, 3H), 2.27-2.14 (m, 1 H), 1.97-1.77 (m, 2 H), 1.76-1.66

ⁱ³C NMR ( 100 MHz, CDC1₃) 6 199.6,

148.9, 139.3, 130.2, 125.7, 43.9, 40.6, 38.2, 36.3, 30.6, 27.6, 25.6, 25.5, 21.4 (2C), 14.6, 8.3 (2C) ; HRMS (ESI) calc for C 17H27O [M+Hl⁺247.2056, found 247.2054.

Example 2

Preparation of l-(8,8a-Dimethyl- 1,2,3, 4,4a, 7,8,8a-octahydronaphthalen-2- yl)ethan-l-one ( lr)

A solution of α,β-unsaturated ketone la (0.5 g, 2.45 mmol) in THF (20 mL) was added to liquid ammonia (20 mL) at -78 °C. Sodium (0.67 g, 29.4 mmol) was added in small pieces and reaction mixture was stirred at -78 °C for 1 h. After consumption of starting material (by TLC), solid NH₄CI (1.0 g) was added and ammonia was allowed to evaporate at room temperature (23°C). Water ( 10 mL) was added and reaction mixture was extracted with EtOAc (3 ^χ 20 mL). The combined organic layer was washed with brine (20 mL), dried over a₂S0 , and solvent was concentrated to afford ketoneas 1 : 1 mixture of diastereomers. The crude material was treated with K2CO3 (1.35 g, 9.80 mmol) in MeOH (20 mL) and refluxed for 2 h. Solvent was removed under vacuum and crude residue was diluted with water (10 mL), and extracted with ether (2 ^χ 30 mL). The combine organic layers was washed with brine (20 mL) and dried over anhydrous a2SC>4. Purification by flash chromatography over silica gel (05:9.5; EtOAc-hexanes) afforded lr (368 mg, 73%) as a colourless oil. IRu_max(film): 1709, 1453, 1352 cm ⁱ; Ή NMR (400 MHz, CDC1₃) δ 5.59-5.48 (m, 2 H), 2.46- 2.40 (m, 1 H), 2.13 (s, 3 H), 2.02-1.97 (m, 2 H), 1.88-1.84 (m, 1 H), 1.78-1.72 (m, 2 H), 1.63-1.53 (m, 1 H), 1.34-1.23 (m, 2 H), 1.06-1.00 (m, 2 H), 0.83- 0.81 (m, 6 H); NMR (100 MHz, CDC1₃) δ 212.5, 131.1 , 125.2, 46.4, 44.1 , 38.2, 34.6, 32.6, 29.9, 28.7, 28.1 , 27.2, 21.6, 14.6; HRMS (ESI) calc for Ci H₂3O[M+H] ⁺207.1743, found 207.1743.

EXAMPLE 3

Preparation of (4.R,4aS,6-R)-6-Acetyl-4,4a-dimethyl-4,4a,5,6,7,8-hexahydro naphthalen-2(3H)-one( Is) and ( 1 S,4aJ?,7jR,8aiR)-7-Acetyl- l,8a-dimethyl- 4a,5,6,7,8,8a-hexahydronaphthalen-2(lH)-one (le)

To a solution of the ketone ( lr) (0.2 g, 0.97 mmol) in benzene (20 mL) at 15 °C were added PDC ( 1.8 g, 4.85mmol) and 'BuOOH (2.0 mL). After the reaction mixture stirred for 15min, it was brought to ambient temperature 28°C and further stirred for 24 h. The reaction mixture was diluted with ether (30 mL), filtered through a celite bed, and washed with ethyl acetate (2 x 10 mL).The filtrate was. concentrated in vacuo. Purification by flash chromatography over silica gel (2:8; EtOAc-hexanes) afforded (I s) ( 134 mg, 63%) and (le) (17 mg, 8 %) as a colourless oils.

Is: IRu_max(film): 1708, 1665, 1354 cm-'; Ή NMR (400 MHz, CDC1₃) δ 5.77 ( s, 1 H), 2.77-2.71 (m, 1 H), 2.52-2.38 (m, 2 H), 2.28-2.25 (m, 2 H), 2. 19 (s, 3 H), 2.10-2.01 (m, 3 H), 1.49-1.38 (m, 1 H), 1.25-1.21 (m, 1 H), 1.10 (s, 3 H), 0.97 (d, J = 6.7 Hz, 3 H); NMR ( 100 MHz, CDC1₃) δ 210.7, 199.4, 168.7, 125.3, 48.8, 42.1 , 40.3, 40.0, 38.9, 32.1 , 28.6, 28.3, 16.8, 15.0.; HRMS (ESI) calc for C_l4H₂i0₂ [M+H] ⁺ 221.1536, found 221.1534. le: IRu_max(film): 1708, 1675, 1451 , 1354 cm-'; »H NMR (400 MHz, CDCI3) 6 6.75 (dd, J = 5.7 Hz, 10.0 Hz, 1 H), 5.91 (d, J = 10.3 Hz, 1 H), 2.71 (m, 1 H), 2.46 (tt, J = 12.3 Hz, 2.7 Hz, 1 H), 2.16 (s, 3 H), 2.05-1.97 (m, 2 H), 1.94-1.86 (m, 2 H), 1.50-1.35 (m, 2 H), 1.17-1.08 (m, 1 H), 1.04 (d, J = 6.7 Hz, 3 H), 0.89 (s, 3 H); i 3C NMR ( 100 MHz, CDCI3) 6 21 1.1 , 201.6, 150.6, 127.8, 46.5, 45.0, 43.3, 38.8, 38.2, 28.3, 28.0, 27.2, 23.2, 6.7; HRMS (ESI) calc for C 1₄H21O2 [M+H]^÷ 221.1536, found 221.1534.

Example 4

Preparation of Compound (4R,4aR)-6-acetyl-4,4a-dimethyl-4,4a,7,8- tetrahydronaphthalen-2(3H)-one (If)

Compound If is prepared by the process as given in example 3 using la as starting material instead of lr.

Yield: 52%; IRu_max(film): 1708, 1675, 1451 , 1354, 1 163 cm-', *H NMR (400 MHz, CDCI3) δ 6.76 (s, 1 H), 5.88 (s, 1 H), 2.78-2.84 (m, 1 H), 2.44-2.51 (m, 2 H), 2.38-2.41 (m, 2 H), 2.34 (s, 3 H), 2.10-2.22 (m, 2 H), 1.23 (s, 3 H), 1.12 (d, J = 6.78 Hz, 3 H). NMR (100 MHz, CDC1₃) δ 198.7, 198.5, 168.3, 143.5, 138.0, 125.0, 42.3, 40.8, 37.3, 30.1 , 25.5, 24.8, 18.9, 15.3. GCMS: 218.

Example 5

Preparation of (±) Nootkatone (7)

To a suspension of methyltriphenylphosphonium bromide (295 mg,0.818mmol) in 10 mL of dry THF was added potassium tertbutoxide (80 mg ,0.681 mmol ) at 0 °C. After 5 minutes, the solution became canary yellow color, to Is (60 mg, 0.272 mmol) in THF (5.0 mL) was added and allowed to stir at 0 °C for 1 h. The reaction was quenched with H₂0 and extracted with ether (2 X 25 mL). Combined organic layer was washed with water, brine dried, over Na₂S0 _j concentrated in vacuo. Purification by flash chromatography over silica gel (1 :9; EtOAc-hexanes) afforded Compound 7 (37 mg, 65%). Mp: 44-45 °C; IRu_max(film): 2923, 1668, 1606, 1459, 1367, 1247 cm-ⁱ; 'HNMR (400 MHz, CDC13). 8 5.77 (s, l H), 4.74 (s, l H) ,4.72(s, l H), 2.50 (ddt, J = 15.3 Hz, 5.0 Hz, 1.8 Hz, 1 H), 2.40- 2.24 (m,4 H), 2.04-1.89 (m,3 H), 1.74 (s,3 H), 1.40-1.29 (m, l H) 1.1 1 (s,3 H), 0.96 (d, 3 H, J = 6.7 Hz, 3 H); i 3C NMR (100 MHz, CDC1₃) 6 199.9, 170.7, 149.3, 124.8, 109.4, 44.0, 42.2, 40.6, 40.5, 39.5, 33.2, 31.7, 21.0, 17.0, 15.0; GCMS:218.

Example 5

l-(3a,4-Dimethyl-3a,4,5,6,7,7a-hexahydro-lH-inden-2-yl)ethan-l-one (8)

The compound lb (30 mg, 0.16 mmol) and Wilkinson's catalyst [(PPh₃)₃RhCl] (29 mg, 0.03 mmol) were placed in an oven-dried round bottom flask. Dry benzene (5.0 mL) was added via syringe, the flask was then flushed with hydrogen gas to expel the argon. The reaction was allowed to proceed at room temperature (28°C) under hydrogen balloon pressure for 12 h. Upon completion of reaction (monitored by TLC), the mixture was passed through an alumina column and concentrated. Purification by flash chromatography over silica gel (0.5:9.5; EtOAc-Petroleum Ether) afforded (±)-Noreremophilane (8) (25 mg, 82% yield) as acolorless liquid. IRu_max(film): 1668, 1606, 1367 cm-'; *H NMR (400 MHz, C₆D₆) 6 6.30 (d, J = 2.0 Hz, 1 H), 2.57 (dd, J = 16.1 , 8.3 Hz 1 H), 2.43 (ddd, J = 16.1 , 1 1.3, 2.26 Hz, 1 H), 1.97 (s, 3 H), 1.78-1.73 (m, 1 H), 1.44-1.41 (m, 1 H), 1.38-1.35 (m, 1 H), 1.34-1.31 (m, 1 H), 1.22-1.17 (m, 1 H), 1.13-1.1 1 (m, 1 H), 1.10-1.08 (m, 1 H), 0.86-0.85 (m, 1 H), 0.84 (s, 3 H), 0.67 (d, J = 6.7 Hz, 3 H); ⁱ³C NMR ( 100 MHz, C₆D₆) 6 195.6, 153.1 , 143.9, 49.6, 46.5, 36.9, 33.6, 29.3, 25.9, 24.4, 22.2, 17.3 (2C). HRMS (ESI) calc for C₁₃H_{2 1}O [M+H]⁺ 193.1587, found 193.1589.

Example 25

Protocol adopted for the mosquito repellence bioassay Methodology

Mosquito repellence activity was assessed on the basis of protection period (hr) offered by various analogues of Nootkatone against Mosquito bites. The protection period was measured on the basis of the concept" time until the first bite" pioneered by Granette (Comparison of mosquito repellency test under laboratory and field conditions. Granett, P. Proc Ann Meet NJ Mosq Assoc, 1938, vol. 25, 51 ,). Repellence tests were carried out against 3-5 days old, blood starved but sucrose fed (0.5M solution), Ae. aegypti females mosquitoes , drawn from well-established laboratory colony maintained at 27±l°CTemperatureand 70 ± 5% Relative humidity. The light intensity was regulated at 300-500 lux for testing against laboratory, colonized Ae. aegypti, a day biting mosquito. Human volunteer's hand covered with polythene disposable gloves was introduced in the cage containing about 200 hungry mosquitoes. Mosquitoes were allowed to bite on the back of the hand through muslin screen stuck over a small window (2cmx2cm) cutout in the polythene bag. Various analogues of Nootkatone were loaded on the muslin cloth screen instead of direct skin application so as to avoid the potential risk involved in the evaluation of natural products of unknown mammalian toxicity. All the test solutions were made in Analar grade Acetone The muslin cloth screen was first treated with the analogue taking two doses @0.25 mg/cm2 and 0.5mg/cm2 and the solvent was evaporated before use. Control muslin screen was treated with solvent alone. After introduction of the hand covered with the polythene glovewith the treated muslin screen into the mosquito cage, numbers of mosquito bites received in subsequent 5 minutes were counted. In the event of no bites in the initial 5 minutes exposure, the test hand was exposed repeatedly after every consecutive ½hr for 5 minutes test till the time a confirmed bite was received. Number of hours before the receipt of a confirmed bite (Techniques for the evaluation of insect repellents. A critical review (Schreck, C.E, Ann Rev Entomol, 1977, vol 22, 101) represented the protection period offered by the test compound. In control rate of mosquito bite was 10- 12 bites/ min. Above test were repeated with both male and female human volunteers using different mosquito batches. All the tests were carried out at 27± 1 °C temperature between 9.00 - 17.00 hrs.

Table 2

ADVANTAGES OF THE INVENTION

The chemical processes in the art for synthesis of nootkatone and the analogues are lengthy, cumbersome and not industrially feasible. There is a possibility to make better insect repellants with less complex structues than the existing ones. In view of this, there still remains a need in the art for effective insect repellents capable of controlling a variety of pests that is relatively safe for humans, animals, plants, and the environment. Also, the present invention envisages to provide a process for synthesis of nootkatone and its novel analogues of formula (I) that ameliorates the drawbacks of the known processes and provides a simple, short, economical process in high yield and purity.

Claims

1. A compound of general formula (I)

wherein

R, Rl , R3, R4 represents hydrogen or alkyl (C 1-C4);

R2 is selected from hydrogen, alkyl (C 1 -C4), COOR, COOH;

'n' is 1 , 2, or 3;

X is selected from O, S or CH2;

' ' represents a single or double bond;

2. The compounds according to claim 1 , wherein representative compounds comprising: l -((4aR,8R,8aS)-8,8a-dimethyl-3,4,4a,7,8,8a-hexahydronaphthalen-2- yl ethanone (la);

1 -((3aS,4R,7aR)-4-methyl-3a,4,5,7a-tetrahydro- 1 H-inden-2-yl)ethanone (Ic); aR)-4-ethyl-3a,4,5,7a-tetrahydro- lH-inden-2-yl)ethanone

7-Acetyl- l,8a-dimethyl-4a,5,6,7,8,8a-hexahydronaphthalen-2(lH)-one

(4R,4aR)-6-acetyl-4,4a-dimethyl-4,4a,7,8-tetxahydronaphthalen-2(3H)- o

(3aS,4R,7aR)-ethyl-2-acetyl-3a,4,5,7a-tetrahydro-lH-indene-4 carboxylate (Ig);

4,5,7a-tetrahydro-lH-inden-2-yl)ethan-l-one

,4a,7,8,8a-hexahydronaphthalen-2-yl)ethan- 1 -one

a,7,8,8a-hexahydronaphthalen-2-yl)ethan-l-

,7,8,8a-hexahydronapht±ialen-2-yl)ethan-l-one (Ik);

l-(3a,4,5,7a-Tetrahydro-lH-inden-2-yl)ethan-l-one (II);

l-(3,4,4a₎7,8,8a-Hexahydronaphthalen-2-yl)ethan-l-one (Im);

l-(4-Ethyl-3a-methyl-3a,4,5,7a-tetra ydro- lH-inden-2-yl)et±ian-l-one

l-(8-Ethyl-8a-methyl-3,4,4a,7,8,8a-hexahydronaphtJialen-2-yl)ethan-l- one (Io);

l-(3a-Ethyl-4-propyl-3a,4,5,7a-tetrahydro-lH-inden-2-yl)ethan-l-one

opyl-3,4,4a,7,8,8a-hexahydronaphthalen-2-yl)ethan- 1 -

l-(8,8a-Dimethyl-l,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)ethan-l one (Ir);

6-Acetyl-4₎4a-dimethyl-4,4a₎5,6,7,8-hexahydronaphthalen-2(3H)-one (Is).

3. The compound according to claim 1 , wherein said compound exhibit insect repellent activity to control the spread of various tropical diseases.

A simple, short, economical process for synthesis of compounds of the general formula I comprising the steps of: subjecting a mixture of diene (N) and an aldehyde ( ) in dry organic solvent to Diels Alder reaction in presence of BF₃,OEt at -78°C, raising the temperature to room temperature in the range of 23 to 28°C to ob

wherein R l , R3 represents hydrogen or alkyl (C 1 -C3) ; R2 is selected from hydrogen, alkyl (C 1 -C3) , COOR where R is selected from hydrogen, alkyl (C I -C3) , COOH .

'n' is 1 , 2, or 3;

b. dissolving the intermediate (P) of step (a) in methanol at 0°C followed by treating with 15% KOH to obtain compounds la id, Ig- Iq re resented by general formula (Q);

c s-Nydrindanes (n - 1 )

s-Decatins (n = 2)

Q

wherein R2 is selected from hydrogen, alkyl (C 1 -C4), COOR or COOH and R, R l , R3 represents hydrogen or alkyl

(C l -C4) ;

subjecting (la) to allylic oxidation using PDC (Pyridinium dichromate) and 'BuOOH in benzene to afford compounds (If) and ketone (S) ,

treating (la) with Na in liq. NH₃ followed by reacting with K2CO3 and MeOH to obtain (Ir);

subjecting (Ir) to allylic oxidation using PDC and 'BuOOH yielded (Is) and (Ie) in the ratio 9 : 1 followed by separation; f. adding potassium tert-butoxide to a suspension of methyltriphenylphoshonium bromide in dry THF to obtain a canary yellow color solution followed by addition of (Is) in THE at 0°C to yield (±) nootkatone (7);

g. hydrogenating compound (lb) with Wilkinson's catalyst to afford (±) noreremophilane.

5. A pharmaceutical composition for repelling or killing insects comprising compounds of formula (I) according to claim 1 , together with carrier and other excipients.

6. Use of compounds of formula (I) according to claim 1 , for repelling or killing insects.